Phenylethanol Glycosides from Cistanche tubulosa Modulate the Gut Microbiota and Cecal Metabolites to Ameliorate Diabetic Nephropathy Induced by Streptozotocin Combined with High-Fat Diet in Rats

Diabetic nephropathy (DN) is a prevalent complication and serious microvascular of diabetes mellitus. After previous studies, we found that phenylethanol glycosides (CPhGs) derived from Cistanche tubulosa (Schenk) Wight exerts antidiabetic and renoprotective effects. However, the effects of CPhGs on DN remain incompletely understood. The study aimed to examine the effects of CPhGs on DN in rats and explore the underlying mechanism involved. A DN rat model was established by streptozotocin (STZ) combined with a high-fat diet. Reagent kits were used to assess the extent to which CPhGs ameliorate hyperglycemia, insulin resistance (IR), renal dysfunction, kidney oxidative stress, and peripheral inflammation. Histology and immunohistochemical staining were used to detect the changes in renal tissue structure and the expression levels of α-smooth muscle actin (α-SMA) and collagen I. Furthermore, we analyzed the cecal contents of DN rats to investigate the effect of CPhGs on gut microbiota by using 16S rRNA sequencing and broad-spectrum metabolite profiling. The results showed that CPhGs demonstrated a range of advantageous outcomes in DN, encompassing the enhancement of kidney function and alleviation of hyperglycemia, IR, renal injury, oxidative stress, and peripheral inflammatory reactions. In addition, CPhGs regulated the abundance of the [Eubacterium]_coprostanoligenes_group, Oscillospiraceae_UCG-005, etc. to modulate the gut microbiota. CPhGs significantly upregulated the content of vitamin B6 and tyrosyl-tryptophan and downregulated histamine, L-methionine, etc. In summary, the therapeutic efficacy of CPhGs on DN rats may be achieved by modulating the gut microbiota and cecal metabolites to restore the metabolic disorders of vitamin B6, histidine, etc.